Knockdown of KPNA2 inhibits autophagy in oral squamous cell carcinoma cell lines by blocking p53 nuclear translocation

Abstract

Oral squamous cell carcinoma (OSCC), one of the 10 most common types of neoplasms in the US, constitutes ~90% of all cases of oral malignancies. Chemoresistance and metastasis are difficult to avoid during the course of treatment, leading to a poor prognosis and a high mortality rate for patients with OSCC. Autophagy, a critical conserved cellular process, has been reported to be highly associated with the regulation of chemoresistance and metastasis of cancer cells. The present study investigated the role of karyopherin α2 (KPNA2), a member of the importin α family, which may serve an important role in p53 nucleocytoplasmic transport in the process of OSCC autophagy. In the CAL-27, SCC-15 and Tca8113 OSCC cell lines, we observed that the downregulation of KPNA2 suppressed cell migration and cisplatin resistance, using wound-healing, Transwell and CCK-8 assays. Additionally, the results of western blot analysis and transmission electron microscopy (TEM) analysis indicated that the knockdown of KPNA2 inhibited autophagy. We confirmed that the inhibition of autophagy with anti-autophagy agents decreased the migration and cisplatin resistance of OSCC cells. We hypothesized that the suppression of cell migration and cisplatin resistance induced by KPNA2 knockdown may be associated with the inhibition of autophagy. To identify the underlying mechanism, further experiments determined that KPNA2 affects the level of autophagy via regulating the p53 nuclear import. Thus, the present study demonstrated that the function of KPNA2 in the process of autophagy may be p53-dependent, and by regulating the translocation of p53, KPNA2 can support autophagy to promote the chemoresistance and metastasis of OSCC cells.

Overexpression of Karyopherin Subunit alpha 2 (KPNA2) Predicts Unfavorable Prognosis and Promotes Bladder Cancer Tumorigenicity via the P53 Pathway

“…Apoptosis of Cal-27 cells is induced by KPNA2 through P53 in tongue squamous cell carcinoma [45]. Interaction between KPNA2 and P53 decreases autophagy of oral squamous cell carcinoma cells [46]. In the present study, WB detection revealed that the deletion of KPNA2 upregulated P53, P21, BAX, and cleaved-caspase3, and downregulated pro-caspase, BCL2, and CyclinD1, whereas the opposite results were found after overexpression of KPNA2.…”

A 4‐gene prognostic signature predicting survival in hepatocellular carcinoma

“…Yang et al 22 suggested knockdown of KPNA2 suppressed the prolifera- tion of HCC cells. Meanwhile, KPNA2 was also demonstrated to be associated with the proliferation of other human cancers including oral squamous cell carcinoma, 23 ovarian cancer, 24 colorectal cancer, 25 etc. Elevated expression of CDC20 was also demonstrated to be related with the development and progression of HCC, 26 and it was also associated with poor survival of others cancers like osteosarcoma, 27 breast cancer, 28 gastric cancer, 29 etc.…”

PHY34 inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer

“…6F ). KPNA2 interacts with CAS during nuclear-cytoplasmic transport, and KPNA2 loss is associated with autophagy inhibition due to cytoplasmic accumulation of wild-type p53 [ 47 , 48 ]. In order to determine if PHY34 treatment changes p53 localization due to loss of KPNA2, we performed immunoblotting after nuclear-cytoplasmic fractionation.…”